gms | German Medical Science

Background: Systemic Lupus erythematosus (SLE) is an autoimmune disease characterized by activated autoreactive lymphocytes and autoantibody production, resulting in tissue damage in multiple organs. A frequent observed severe manifestation is Lupus nephritis (LN), possibly resulting in limited kidney function or even acute renal failure. Type I and III interferons, which are both part of the antiviral defense, have both been associated with the disease’s activity. In sera and urine of SLE patients an enhanced level of IL-28/29 was described, but their distinct functional role in the course of disease need to be further investigated.

Methods: As model system for SLE MRL Faslpr mice were used. These mice develop severe symptoms, such as ANAs (Anti-nuclear antibodies), lymphadenopathy, splenomegaly, skin lesions and immunocomplex glomerulonephritis. To determine the role of type I and III interferons during onset and progression of autoimmunity – with focus on the development of Lupus nephritis (LN) – the expression of the IFNs and their specific receptors (IFNαR and IL-28R) was observed on RNA level (via qPCR) and on protein level (via immunohistochemistry) in MRL Faslpr mice. Furthermore MRL Faslpr mice deficient of the IL-28R and/or IFNαR were generated. The progression of autoimmunity in the knockout mice was monitored and compared to their wild type littermates. The pathophysiology of the kidney was histologically examined (PAS/HE staining; Immunohistochemistry).

Results: So far we could confirm the expression of IL-28 and it’s receptor in the kidney of MRL Faslpr mice. The overall IL-28 mRNA expression increased with disease activity in renal tissue, similar to the IL-28R mRNA expression in the spleen. In preliminary studies with MRL Faslpr IL-28R -/- mice, a less extenuated lymphadenopathy and albuminuria was observed compared to their wildtype littermates. The histopathological examination of the kidneys (3 month of age) suggests a slower progression of Lupus nephritis in IL-28R knockout mice. Similar results were obtained in MRL Faslpr IFNαR-/- and further in MRL Faslpr IL-28R -/- IFNαR -/- mice. One of the regulatory mechanisms of interferon expression is the destabilization of their mRNA by the RNA binding protein KH-type splicing regulatory protein (KSRP). Hence KSRP could display a potential protective role in the development of autoimmunity. In line with this hypothesis we could observe an enhanced kidney damage and an increased number of kidney infiltrating cells in MRL Faslpr KSRP knock out mice, compared to wild type littermates. Interestingly the Lymphadenopathy was decreased in MRL Faslpr KSRP knock out mice.

Conclusion: So far our results suggest a participation of type III IFNs in the development of Lupus nephritis in MRL Faslpr mice. Further studies will be performed to reveal their potential immunomodulatory functions and influence on the cytokine/chemokine milieu. The subsequent aim is to transfer the results obtained in the murine model to human SLE and to evaluate IL-28 as disease activity marker.